<i>TERT</i>promoter mutations are associated with poor prognosis and cell immortalization in meningioma

Spiegl-Kreinecker, Sabine; Lötsch, Daniela; Neumayer, Katharina; Kastler, Lucia; Gojo, Johannes; Pirker, Christine; Pichler, Josef; Weis, Serge; Kumar, Rajiv; Webersinke, Gerald; Gruber, Andreas J.; Berger, Walter

doi:10.1093/neuonc/noy104

Cited by 99 publications

(82 citation statements)

References 44 publications

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“…As the current WHO grading system is not sufficient to predict the clinical course, reliable biomarkers have been sought. A particularly interesting target are TERT -alt including promoter mutations5 7–11 and gene translocations 12…”

Section: Introductionmentioning

confidence: 99%

“…TERT mutations occur in specific ‘hotspots’ of the promoter ( TERT p) region known as C228T and C250T (chromosomal positions 1,295,228 and 1,295,250). These C>T transition mutations result in new binding sites for a specific transcription factor family known as E-twenty-six (ETS), which leads to maintenance of the telomere length as binding of ETS-transcription factors is involved in the upregulation of TERT expression 5 11 13. Similarly, genomic rearrangements that have led to LPCAT1-TERT and RETREG1-TERT fusions also upregulate TERT expression 8 12.…”

Section: Introductionmentioning

confidence: 99%

“…The incidence of TERT -alt has not yet been studied in consecutively collected meningioma tumour samples, but ranges from 6.3% to 9.8% in the largest cohorts hitherto investigated 5 7 10 11. Interestingly, all previous studies consistently show a higher risk of recurrence in patients with TERT -alt meningiomas compared with their wild-type ( TERT p-wt) counterpart, but the majority of these studies have incompletely discussed other clinically important differences, such as survival effects and patient characteristics, primarily due to small study cohorts.…”

Section: Introductionmentioning

confidence: 99%

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Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis

Mirian¹,

Duun‐Henriksen

Juratli

et al. 2020

J Neurol Neurosurg Psychiatry

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BackgroundTERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought.MethodsWe applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs.ResultsTERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients.ConclusionsTERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification.Trial registration numberPROSPERO: CRD42018110566.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis

Mirian¹,

Duun‐Henriksen

Juratli

et al. 2020

J Neurol Neurosurg Psychiatry

Self Cite

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“…TERT mutation also has been reported in meningiomas, especially in recurrent and high grade (grades II and III) tumors [20]. Although an overall incidence of TERT mutation is low (around 5%) in meningioma, TERT mutation predicted more aggressive behavior and poor prognosis in meningioma [21,22].…”

Section: Discussionmentioning

confidence: 96%

Adjunctive markers for classification and diagnosis of central nervous system tumors: results of a multi-center neuropathological survey in Korea

Jin

Kim

2020

J Pathol Transl Med

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Background: The revised 4th 2016 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) classification has adopted integrated diagnosis encompassing the histology and molecular features of CNS tumors. We aimed to investigate the immunohistochemistry, molecular testing, and testing methods for diagnosis of CNS tumors in pathological labs of tertiary centers in Korea, and evaluate the adequacy of tests for proper diagnosis in daily practice. Methods: A survey, composed of eight questions concerning molecular testing for diagnosis of CNS tumors, was sent to 10 neuropathologists working in tertiary centers in Korea. Results: For diagnosis of astrocytic and oligodendroglial tumors, all 10 centers performed isocitrate dehydrogenase mutations testing and 1p/19q loss of heterozygosity. For glioneuronal tumors, immunohistochemistry (IHC) assays for synaptophysin (n = 9), CD34 (n = 7), BRAF(VE1) (n = 5) were used. For embryonal tumors, particularly in medulloblastoma, four respondents used IHC panel (growth factor receptor bound protein 2-associated protein 1, filamin A, and yes-associated protein 1) for molecular subclassification. Regarding meningioma, all respondents performed Ki-67 IHC and five performed telomerase reverse transcriptase promoter mutation. Conclusions: Most tertiary centers made proper diagnosis in line with 2016 WHO classification. As classification of CNS tumors has evolved to be more complex and more ancillary tests are required, these should be performed considering the effect of necessity and justification.

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“…In grade I meningioma, TERT C228T and C250T mutations are linked with transformation to higher grades (20), prompting many scientists and clinicians to consider standardized testing for these specific changes. Further studies demonstrate that the presence of C228T and C250T correlates with increased TERT mRNA and functional increases in telomerase activity (21), and in Grade II or III tumors, univariate analysis revealed a significant association with decreased progression-free survival (PFS, median 12.5 vs. 26 months, p = 0.004) and overall survival (OS median 26 vs. 46 months, p = 0.009) (22). In vitro, TERT mutated meningioma cells show decreased TERT activity in response to YK-4-279, a small molecule inhibitor of ETS transcription factor, suggesting a novel potential strategy for targeting these aggressive tumors.…”

Section: Nf2-mutated Meningiomamentioning

confidence: 93%

Recent Advances in Meningioma Immunogenetics

2020

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Meningiomas are relatively common, and typically benign intracranial tumors, which in many cases can be cured by surgical resection. However, less prevalent, high grade meningiomas, grow quickly, and recur frequently despite treatment, leading to poor patient outcomes. Across tumor grades, subjective guidelines for histological analysis can preclude accurate diagnosis, and an insufficient understanding of recurrence risk can cloud the choice of optimal treatment. Improved diagnostic and prognostic markers capable of discerning between the 15 heterogeneous WHO recognized meningioma subtypes are necessary to improve disease management and identify new targeted drug treatments. In this review, we show the advances in molecular profiling and immunophenotyping of meningiomas, which may lead to the development of new personalized therapeutic strategies.

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TERTpromoter mutations are associated with poor prognosis and cell immortalization in meningioma

Abstract: TERT promoter mutations drive meningioma aggressiveness, resulting in reduced patient survival, but might also open novel therapeutic options for progressive disease.

Cited by 99 publications

References 44 publications

Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis

Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis

Adjunctive markers for classification and diagnosis of central nervous system tumors: results of a multi-center neuropathological survey in Korea

Recent Advances in Meningioma Immunogenetics

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